This new program will focus on the development of a novel strategy for the enantioselective synthesis of complex medium ring ether marine natural products. A practical asymmetric aldol addition followed by a ring closing metathesis reaction will be used to construct six to nine membered cyclic ethers. The ring closing metathesis reaction of medium rings can be effected without cyclic constraints by exploiting the gauche effect of adjacent oxygen substituents. This effect will be explored in a tandem ring opening-ring closing metathesis reaction for the simultaneous production of two medium-sized cyclic ethers. The methods for medium ring ether synthesis will be utilized in the synthesis of a variety of novel, pharmacologically active marine natural products such as isolaurallene, pannosallene, brevetoxin A, mucocin and gigantecin. Since many of the polyether toxins and the cytotoxic annonaceous acetogenins are available in very small quantities, chemical synthesis offers one solution to the supply problem for further studies on the mechanism of action and chemical modification of the toxins and antitumor agents, leading ultimately to improvements in public health.